EP0127529A2 - Aminocyclic N-oxide derivatives, process for their preparation and their therapeutical use - Google Patents

Aminocyclic N-oxide derivatives, process for their preparation and their therapeutical use Download PDF

Info

Publication number
EP0127529A2
EP0127529A2 EP84401032A EP84401032A EP0127529A2 EP 0127529 A2 EP0127529 A2 EP 0127529A2 EP 84401032 A EP84401032 A EP 84401032A EP 84401032 A EP84401032 A EP 84401032A EP 0127529 A2 EP0127529 A2 EP 0127529A2
Authority
EP
European Patent Office
Prior art keywords
alkyl
alkyloxy
formula
compounds
equatorial
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP84401032A
Other languages
German (de)
French (fr)
Other versions
EP0127529A3 (en
Inventor
Philippe Dostert
Thierry Imbert
Bernard Bucher
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Synthelabo SA
Original Assignee
Delalande SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Delalande SA filed Critical Delalande SA
Publication of EP0127529A2 publication Critical patent/EP0127529A2/en
Publication of EP0127529A3 publication Critical patent/EP0127529A3/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/94—Oxygen atom, e.g. piperidine N-oxide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/14—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof

Definitions

  • the present invention relates to new N-oxides of aminocyclic derivatives, their preparation process and their application in therapy.
  • the oxidation is carried out by using a peracid such as metachloro-perbenzoric acid or a peroxide such as hydrogen peroxide; when using metachloroperbenzoic acid, it is preferably carried out in an aprotic solvent such as methylene chloride and at low temperature such as 0 ° C. and when using hydrogen peroxide, it is preferably carried out at reflux in a aprotic solvent such as acetonitrile.
  • a peracid such as metachloro-perbenzoric acid or a peroxide such as hydrogen peroxide
  • the separation of forms (la) and (Ib) can in particular be carried out by column chromatography, preferably by liquid chromatography on a silica column, at high or medium pressure, the separate forms being identified by their spectral properties, using NMR spectra
  • the compounds according to the invention have been studied in laboratory animals and have shown activity on the central nervous system, in particular a neuroleptic action.
  • mice have been demonstrated in mice, in particular by the test of antagonism to rectifications with apomorphine carried out according to the protocol described by G. GOURET and Coll. in J. Pharmacol. (Paris) ( 1973 ), 4, 34 1 .
  • the difference between the toxic doses and the active doses allows the use of the compounds (I) as medicaments, in particular in the treatment of mental disorders, in particular as neuroleptics.
  • the present invention therefore also relates, as medicaments, to the compounds of formula (I) which are pharmaceutically acceptable.
  • the invention extends to pharmaceutical compositions containing, as active principle, at least one of the medicaments defined above, in combination with a pharmaceutically acceptable vehicle.
  • compositions can be administered in particular (a) orally in the form of tablets, dragees or capsules each containing up to 300 mg of active principle (up to 8 tablets, dragees or capsules per day) or in the form of a solution containing 0.1 to 1% of active ingredient (up to 60 drops, one to three times a day) or (b) parenterally in the form of injectable ampoules each containing up to 100 mg of active ingredient (up to 8 vials per day).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Neurology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Anesthesiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

N-Oxides of aminocyclic derivatives corresponding to the formula: <IMAGE> in which n = 2 or 3; R = H, halogen(s), C1-C4 alkyl, C1-C4 alkoxy, CN or CF3, and Ar = substituted pyrimidine or substituted phenyl group. These compounds are useful as medications especially as neuroleptics.

Description

La présente invention a pour objet de nouveaux N-oxydes de dérivés aminocycliques, leur procédé de préparation et leur application en thérapeutique.The present invention relates to new N-oxides of aminocyclic derivatives, their preparation process and their application in therapy.

Plus précisément, les nouveaux composés selon l'invention répondent à la formule :

Figure imgb0001
dans laquelle R représente un atome d'hydrogène, un ou deux atomes d'halogène ou un groupe alkyle en C1-C4, alkyloxy en C1-C4, cyano ou trifluorométhyle, n prend la valeur 2 ou 3 et Ar représente :

  • a) un groupe pyrimidinique de formule :
    Figure imgb0002
    où R = H, alkyle en C1-C4, alkoxy en C1-C4, NH2, NH-alkyl en C1-C4, N(alkyl en C1-C4)2, pyrrolidino, pipéridino ou morpholino et R2 = alkyle en C1-C4;
  • b) un groupe aromatique de formule :
    Figure imgb0003
    où p = 1 ou 2, R2 a les mêmes significations que précédemment, R3 = CH, alkyloxy en C1-C4 ou alkyle en C1-C4 et R 4 = halogène, OH, alkyloxy en C1-C4, alkylsulfonyle en C1-C4, N02, CN, CHO, (alkyl en C1-C4) carbonyle, NH2, NH-alkyl en C1-C4, N(alkyl en C1-C4)2, pyrrolidino, morpholino, pipéridino, SO2NH2, SO2 N(alkyl en C1-C4)2, pyrrolidinosulfonyle, pipéridinosulfonyle ou morpholinosulfonyle,
    R3 pouvant en outre représenter un groupe NH2 ou NH-alkyl en C1-C4 quand R4 = halogène et un atome d'hydrogène quand R4 représente un groupe OH ou alkyloxy en C1-C4;
  • c) un groupe aromatique de structure :
    Figure imgb0004
    où R2 et p ont les mêmes significations que précédemment, R'3 = OH, alkyloxy en C1-C4 ou alkyle en C1-C4 et R5 = NH2, NH-alkyl en C1-C4, N(alkyl en C1-C4)2, pyrrolidino, pipéridino, morpholino, halogène ou alkyloxy en C1-C4, R'3 pouvant en outre représenter un atome d'hydrogène quand R5 représente un groupe alkyloxy en C1-C4; ou
  • d) un groupe aromatique de structure :
    Figure imgb0005
    où R a la même signification que précédemment.
More specifically, the new compounds according to the invention correspond to the formula:
Figure imgb0001
 wherein R represents a hydrogen atom, one or two halogen atoms or alkyl C 1 -C 4 alkyloxy, C 1 -C 4 alkyl, cyano or trifluoromethyl, n is 2 or 3 and Ar represents :
  • a) a pyrimidine group of formula:
    Figure imgb0002
     where R = H, C 1 -C 4 alkoxy, C 1 -C 4, NH 2, NH-C 1 -C 4 alkyl, N (C 1 -C 4 alkyl) 2 pyrrolidino, piperidino or morpholino and R 2 = C 1 -C 4 alkyl;
  • b) an aromatic group of formula:
    Figure imgb0003
     where p = 1 or 2, R 2 has the same meanings as above, R 3 = CH, C 1 -C 4 alkyloxy or C 1 -C 4 alkyl and R 4 = halogen, OH, C 1 -C alkyloxy 4 , C 1 -C 4 alkylsulfonyl, N0 2 , CN, CHO, (C 1 -C 4 alkyl) carbonyl, NH 2 , NH-C 1 -C 4 alkyl, N (C 1 -C 4 alkyl) 2 , pyrrolidino, morpholino, piperidino, SO 2 NH 2 , SO 2 N (C 1 -C 4 alkyl) 2 , pyrrolidinosulfonyl, piperidinosulfonyl or morpholinosulfonyl,
    R 3 can also represent an NH 2 or NH-C 1 -C 4 alkyl group when R 4 = halogen and a hydrogen atom when R 4 represents an OH or C 1 -C 4 alkyloxy group;
  • c) an aromatic group with a structure:
    Figure imgb0004
     where R 2 and p have the same meanings as above, R ' 3 = OH, C 1 -C 4 alkyloxy or C 1 -C 4 alkyl and R 5 = NH 2 , NH-C 1 -C 4 alkyl, N (C 1 -C 4 alkyl) 2 , pyrrolidino, piperidino, morpholino, halogen or C 1 -C 4 alkyloxy, R ′ 3 possibly also representing a hydrogen atom when R 5 represents a C 1 alkyloxy group -C 4 ; or
  • d) an aromatic group with a structure:
    Figure imgb0005
     where R has the same meaning as before.

Il est à noter que les composés selon l'invention :

  • - se présentent sous la forme axiale (Ia):
    Figure imgb0006
     où la chaîne ArCONH est en position équatoriale et l'atome d'oxygène du fragment
    Figure imgb0007
    est en position axiale ou sous la forme équatoriale (Ib) :
    Figure imgb0008
    où la chaîne ArCONH et l'atome d'oxygène du fragment
    Figure imgb0009
    sont tous deux en position équatoriale ; ou
  • - sont constitués par un mélange de la forme axiale (Ia) et de la forme équatoriale (Ib).
It should be noted that the compounds according to the invention:
  • - are in the axial form (I a ):
    Figure imgb0006
     where the ArCONH chain is in an equatorial position and the oxygen atom of the fragment
    Figure imgb0007
     is in the axial position or in the equatorial form (Ib):
    Figure imgb0008
     where the ArCONH chain and the oxygen atom of the fragment
    Figure imgb0009
     are both in an equatorial position; or
  • - consist of a mixture of the axial shape (Ia) and the equatorial shape (Ib).

Les composés de formule (I) selon l'invention peuvent être obtenus par oxydation des composés de formule :

Figure imgb0010
dans laquelle la chaîne ArCONH est en position équatoriale, n = 2 ou 3 et R et Ar ont la même signification que dans la formule (I), éventuellement suivie de la séparation des formes (la) et (Ib).The compounds of formula (I) according to the invention can be obtained by oxidation of the compounds of formula:
Figure imgb0010
 in which the chain ArCONH is in the equatorial position, n = 2 or 3 and R and Ar have the same meaning as in formula (I), optionally followed by the separation of the forms (la) and (Ib).

Avantageusmpnt, on réalise l'oxydation par mise en oeuvre d'un peracide tel que l'acide métachloro- perbenzorque ou d'un peroxyde tel que l'eau oxygénée; quand on utilise l'acide métachloroperbenzoï- que, on opère de préférence dans un solvant aprotique tel que le chlorure de méthylène et à basse température telle que 0° C et quand on utilise l'eau oxygénée, on opère de préférence au reflux dans un solvant aprotique tel que l'acétonitrile.Advantageously, the oxidation is carried out by using a peracid such as metachloro-perbenzoric acid or a peroxide such as hydrogen peroxide; when using metachloroperbenzoic acid, it is preferably carried out in an aprotic solvent such as methylene chloride and at low temperature such as 0 ° C. and when using hydrogen peroxide, it is preferably carried out at reflux in a aprotic solvent such as acetonitrile.

La séparation des formes (la) et (Ib) peut être notamment réalisée par chromatographie sur colonne, de préférence par chromatographie liquide sur colonne de silice, à haute ou moyenne pression, les formes séparées étant identifiées par leurs propriétés spectrales, notamment à l'aide des spectres de R.M.N.The separation of forms (la) and (Ib) can in particular be carried out by column chromatography, preferably by liquid chromatography on a silica column, at high or medium pressure, the separate forms being identified by their spectral properties, using NMR spectra

Les composés de formule (II) sont quant à eux obtenus conformément aux protocoles opératoires décrits dans les brevets français 2 446 823, 2 476 088 et 2 493 848.The compounds of formula (II) are obtained in accordance with the operating protocols described in French patents 2,446,823, 2,476,088 and 2,493,848.

Les préparations suivantes sont données à titre d'exemple non limitatif pour illustrer l'invention.The following preparations are given by way of nonlimiting example to illustrate the invention.

N-oxyde axial du (diméthoxy-2,3) benzoylamino-3 N-benzyl aza-8 bicyclo [3.2,1] octane [(Ia), numéro de code 1] et N-oxyde équatorial du (diméthoxy-2,3) benzoylamino-3 N-benzyl aza-8 bicyclo[3.2.1] octane [(Ib) , numéro de code 2]Axial N-2,3-dimethyloxy benzoylamino-3 N-Benzyl aza-8 bicyclo [3.2,1] octane [(Ia), code number 1] and Equatorial N-oxide of 2,3-dimethoxy ) benzoylamino-3 N-benzyl aza-8 bicyclo [3.2.1] octane [(Ib), code number 2]

①A une solution de 6,5 g deβ-(diméthoxy-2,3) benzoylamiro-3 N-benzyl aza-8 bicyclo [3.2.1] octane (II) dans 150 ml de chlorure de méthylène refroidie à 0° C, on ajoute 3,6 g d'acide métachloroperbenzofque ; on laisse 10 minutes en contact, puis on lave à l'aide de NaOH 1 N, décante, sèche la phase organique sur sulfate de sodium, filtre et évapore le filtrat. L'huile brute obtenue est chromatographiée sur une colonne de silice (chromatographie liquide à moyenne pression). Par élution à l'aide du mélange chlorure de méthylène 95 % - méthanol 5 %, on obtient (a) 4,5 g (66 %) du N-oxyde axial (la) (numéro de code 1) que l'on recristallise dans le pentane:

  • . Point de fusion : 210° C
  • . Formule brute : C23H28N2O4
  • . Poids moléculaire : 396,47
  • . Spectre de R.M.N. (à 250 MHz ; CD3OD) δ ppm =
  • . entre 7,05 et 7,65, m, (8 protons benzéniques et CONH)
  • . 4,5, m, proton axial en 3
  • . 4,42, s, -CH2 benzylique
  • . 3,82 et 3,88, s, 2 CH30
  • . 3,53, s, 2 protons tropaniques en 1 et 5
  • . 2,5, m, protons tropaniques axiaux en 2 et 4 et 2 protons tropaniques en 6 et 7
  • . 2,25, m, 2 protons tropaniques en 6 et 7
  • 1,92, m, 2 protons tropaniques équatoriaux en 2 et 4
    puis (b) 1,2 g (17 %) du N-oxyde équatorial (Ib) (numéro de code 2) que l'on recristallise dans l'éther éthylique:
  • . Point de fusion : 235° C
  • . Formule brute : C23H28N2O4
  • . Poids moléculaire : 396,47
  • . Spectre de R.M.N. (à 250 MHz ; CD3OD) δ ppm =
    • . 7,83, m, CONH
    • . entre 7,12 et 7,45, m, 8 protons benzéniques
    • . 4,8, s, CH2 benzylique
    • . 4,5, m, proton tropanique axial en 3
    • . 3,88 et 3,91, s, 2 CH3O
    • . 3,6, s, 2 protons tropaniques en 1 et 5
    • . entre 2,5 et 2,7, m, 2 protons tropaniques axiaux en 2 et 4 et 2 protons tropaniques en 6 et 7
    • . 2,13, m, 2 protons tropaniques équatoriaux en 2 et 4
    • . 1,96, m, 2 protons tropaniques en 6 et 7
①A solution of 6.5 g of β- (2,3-dimethoxy) benzoylamiro-3 N-benzyl aza-8 bicyclo [3.2.1] octane (II) in 150 ml of methylene chloride cooled to 0 ° C, add 3.6 g of metachloroperbenzofque acid; it is left in contact for 10 minutes, then washed with 1N NaOH, decanted, the organic phase is dried over sodium sulfate, filtered and the filtrate is evaporated. The crude oil obtained is chromatographed on a silica column (medium pressure liquid chromatography). By elution using a 95% methylene chloride - 5% methanol mixture, one obtains (a) 4.5 g (66%) of the axial N-oxide (la) (code number 1) which is recrystallized in pentane:
  • . Melting point: 210 ° C
  • . Gross formula: C 23 H 28 N 2 O 4
  • . Molecular Weight: 396.47
  • . NMR spectrum (at 250 MHz; CD 3 OD) δ ppm =
  • . between 7.05 and 7.65, m, (8 benzene protons and CONH)
  • . 4.5, m, axial proton in 3
  • . 4.42, s, -CH 2 benzyl
  • . 3.82 and 3.88, s, 2 CH 3 0
  • . 3.53, s, 2 tropanic protons in 1 and 5
  • . 2.5, m, axial tropic protons in 2 and 4 and 2 tropic protons in 6 and 7
  • . 2.25, m, 2 tropanic protons in 6 and 7
  • 1.92, m, 2 equatorial tropanic protons in 2 and 4
    then (b) 1.2 g (17%) of the equatorial N-oxide (Ib) (code number 2) which is recrystallized from ethyl ether:
  • . Melting point: 235 ° C
  • . Gross formula: C 23 H 28 N 2 O 4
  • . Molecular Weight: 396.47
  • . NMR spectrum (at 250 MHz; CD 3 OD) δ ppm =
    • . 7.83, m, CONH
    • . between 7.12 and 7.45, m, 8 benzene protons
    • . 4.8, s, CH 2 benzyl
    • . 4.5, m, axial tropic proton in 3
    • . 3.88 and 3.91, s, 2 CH 3 O
    • . 3.6, s, 2 tropanic protons in 1 and 5
    • . between 2.5 and 2.7, m, 2 axial tropic protons in 2 and 4 and 2 tropic protons in 6 and 7
    • . 2.13, m, 2 equatorial tropanic protons in 2 and 4
    • . 1.96, m, 2 tropanic protons in 6 and 7

② A une solution à 20° C de 26 g deβ-(diméthoxy-2,3) benzoyl amino-3 N-benzyl aza-8 bicyclo [3.2.1] octane (II) dans 300 ml d'acétonitrile, on ajoute lentement 150 ml d'eau oxygénée à 120 volumes. Puis on porte le mélange 30 minutes au reflux. Après refroidissement on ajoute du palladium sur charbon à 5 %, humide, pour détruire l'excès d'eau oxygénée. Puis on filtre, évapore le filtrat et chromatographie le résidu sur colonne de silice (chromatographie liquide à moyenne pression). Par élution par le mélange chlorure de méthylène 95 % - méthanol 5 %, on obtient 9 g (33 %) de N-oxyde axial [(Ia), numéro de code 1J, puis par élution par le mélange chlorure de méthylène 85 % - méthanol 15 %, on obtient 9 g (33 %) de N-oxyde équatorial [(Ib), numéro de code 2] identiques pour les spectres RMN aux produits obtenus par la méthode ①.② To a solution at 20 ° C of 26 g of β- (2,3-dimethoxy) 3-amino benzoyl N-benzyl aza-8 bicyclo [3.2.1] octane (II) in 300 ml of acetonitrile, slowly added 150 ml of hydrogen peroxide at 120 volumes. Then the mixture is brought to reflux for 30 minutes. After cooling, 5% palladium on charcoal, wet, is added to destroy the excess hydrogen peroxide. Then filtered, the filtrate is evaporated and the residue is chromatographed on a silica column (medium pressure liquid chromatography). By elution with a 95% methylene chloride - 5% methanol mixture, 9 g (33%) of axial N-oxide [(Ia), code number 1J are obtained, then by elution with a 85% methylene chloride mixture - 15% methanol, 9 g (33%) of equatorial N-oxide [(Ib), code number 2] identical for the NMR spectra to the products obtained by the method ① are obtained.

Nous noterons ici que l'attribution axiale et équatoriale des N-oxydes (Ia) et (Ib) a été faite selon l'étude RMN des N-oxydes tropaniques décrite dans Helvetica Chimica Acta. 55, 637, (1972).We note here that the axial and equatorial attribution of the N-oxides (Ia) and (Ib) was made according to the NMR study of the tropanic N-oxides described in Helvetica Chimica Acta. 55, 637, (1972).

Par les mêmes procédés ① ou ② précédemment décrits, mais à partir des réactifs correspondants, on obtient les composés de formule (I) de numéros de code 3 à 8, 13 à 16, 18 et 19 répertoriés dans le tableau I suivant.

Figure imgb0011
Figure imgb0012
Figure imgb0013
Figure imgb0014
Figure imgb0015
Figure imgb0016
Figure imgb0017
 By the same methods ① or ② previously described, but from the corresponding reagents, the compounds of formula (I) are obtained with code numbers 3 to 8, 13 to 16, 18 and 19 listed in Table I below.
Figure imgb0011
Figure imgb0012
Figure imgb0013
Figure imgb0014
Figure imgb0015
Figure imgb0016
Figure imgb0017

Les composés selon l'invention ont été étudiés chez l'animal de laboratoire et ont montré une activité sur le système nerveux central, notamment une action neuroleptique.The compounds according to the invention have been studied in laboratory animals and have shown activity on the central nervous system, in particular a neuroleptic action.

Ces propriétés psychotropes ont été mises en évidence chez la souris, notamment par le test de l'antagonisme aux redressements à l'apomorphine réalisé d'après le protocole décrit par G. GOURET et Coll. dans J. Pharmacol. (Paris) (1973), 4, 341.These psychotropic properties have been demonstrated in mice, in particular by the test of antagonism to rectifications with apomorphine carried out according to the protocol described by G. GOURET and Coll. in J. Pharmacol. (Paris) ( 1973 ), 4, 34 1 .

La toxicité aiguë des composés selon l'invention a également été étudiée chez la souris par voie intrapéritonéale. Le tableau II ci-après donne à titre d'exemple non limitatif les résultats obtenus avec certains des composés selon l'invention.

Figure imgb0018
The acute toxicity of the compounds according to the invention has also been studied in mice intraperitoneally. Table II below gives, by way of nonlimiting example, the results obtained with some of the compounds according to the invention.
Figure imgb0018

Comme le montre le tableau ci-dessus, l'écart entre les doses toxiques et les doses actives permet l'emploi comme médicaments des composés (I), notamment dans le traitement des troubles du psychisme, notamment comme neuroleptiques.As shown in the table above, the difference between the toxic doses and the active doses allows the use of the compounds (I) as medicaments, in particular in the treatment of mental disorders, in particular as neuroleptics.

La présente invention a donc également pour objet, à titre de médicaments, les composés de formule (I) pharmaceutiquement acceptables. L'invention s'étend aux compositions pharmaceutiques renfermant, à titre de principe actif, l'un au moins des médicaments définis ci-dessus, en association avec un véhicule pharmaceutiquement acceptable.The present invention therefore also relates, as medicaments, to the compounds of formula (I) which are pharmaceutically acceptable. The invention extends to pharmaceutical compositions containing, as active principle, at least one of the medicaments defined above, in combination with a pharmaceutically acceptable vehicle.

Ces compositions peuvent être administrées en particulier (a) par voie orale sous forme de comprimés, dragées ou gélules contenant chacun jusqu'à 300 mg de principe actif (jusqu'à 8 comprimés, dragées ou gélules par jour) ou sous forme de solution contenant de 0,1 à 1 % de principe actif (jusqu'à 60 gouttes, une à trois fois par jour) ou (b) par voie parentérale sous forme d'ampoules injectables contenant chacune jusqu'à 100 mg de principe actif (jusqu'à 8 ampoules par jour).These compositions can be administered in particular (a) orally in the form of tablets, dragees or capsules each containing up to 300 mg of active principle (up to 8 tablets, dragees or capsules per day) or in the form of a solution containing 0.1 to 1% of active ingredient (up to 60 drops, one to three times a day) or (b) parenterally in the form of injectable ampoules each containing up to 100 mg of active ingredient (up to 8 vials per day).

Claims (12)

1. N-oxydes de dérivés aminocycliques, caractérisés en ce qu'ils répondent à la formule générale :
Figure imgb0019
dans laquelle R représente un atome d'hydrogène, un ou deux atomes d'halogène ou un groupe alkyle en C1-C4, alkyloxy en C1-C4, cyano ou trifluorométhyle, n prend la valeur 2 ou 3 et Ar représente : a) un groupe pyrimidinique de formule :
Figure imgb0020
où R1 = H, alkyle en C1-C4, alkoxy en C1-C4, NH2, NH-alkyl en. C1-C4, N(alkyl en C1-C4)2, pyrrolidino, pipéridino ou morpholino et R2= = alkyle en C1-C4; b) un groupe aromatique de formule :
Figure imgb0021
où p = 1 ou 2, R2 a les mêmes significations que précédemment, R3 = CH, alkyloxy en C1-C4 ou alkyle en C1-C4 et R 4 = halogène, OH, alkyloxy en C1-C4, alkylsulfonyle en C1-C4, N029 CN, CHO, (alkyl en C1-C4) carbonyle, NH2, NH-alkyl en C1-C4, N(alkyl en C1-C4)2, pyrrolidino, morpholino, pipéridino, SO2NH2, S02 N(alkyl en C1-C4)2, pyrrolidinosulfonyle,gipéridinosulfonyle ou morpholinosulfonyle,
R3 pouvant en outre représenter un groupe NH2 ou NH-alkyl. en C1-C4 quand R4 = halogène et un atome d'hydrogène quand R4 représente un groupe OH ou alkyloxy en C1-C4; c) un groupe aromatique de structure :
Figure imgb0022
où R2 et p ont les mêmes significations que précédemment, R'3 = OH, alkyloxy en C1-C4 ou alkyle en C1-C4 et R5 = NH2, NH-alkyl en C1-C4, N(alkyl en C1-C4)2, pyrrolidino, pipéridino, morpholino, halogène ou alkyloxy en C1-C4, R'3 pouvant en outre représenter un atome d'hydrogène quand R5 représente un groupe alkyloxy en C1-C4; ou d) un groupe aromatique de structure :
Figure imgb0023
où R2 a la même signification que précédemment ; les composés de formule (I) possédant la forme axiale (la) :
Figure imgb0024
 où n = 2 ou 3 et la chaîne ArCONH est en position équatoriale et l'atome d'oxygène du fragment
Figure imgb0025
est en position axiale ou la forme équatoriale (Ib) :
Figure imgb0026
où n = 2 ou 3 et la chaîne ArCONH et l'atome d'oxygène du fragment
Figure imgb0027
sont tous deux en position équatoriale ; ou étant constitués par un mélange de la forme axiale (Ia) et de la forme équatoriale (Ib). 1. N-oxides of aminocyclic derivatives, characterized in that they correspond to the general formula:
Figure imgb0019
 wherein R represents a hydrogen atom, one or two halogen atoms or alkyl C 1 -C 4 alkyloxy, C 1 -C 4 alkyl, cyano or trifluoromethyl, n is 2 or 3 and Ar represents : a) a pyrimidine group of formula:
Figure imgb0020
 where R 1 = H, C 1 -C 4 alkoxy, C 1 -C 4, NH 2, NH-alkyl. C 1 -C 4 , N (C 1 -C 4 alkyl) 2 , pyrrolidino, piperidino or morpholino and R 2 = = C 1 -C 4 alkyl; b) an aromatic group of formula:
Figure imgb0021
 where p = 1 or 2, R 2 has the same meanings as above, R 3 = CH, C 1 -C 4 alk y loxy or C 1 -C 4 alkyl and R 4 = halogen, OH, C 1 alkyloxy -C 4 , C 1 -C 4 alkylsulfonyl, N0 29 CN, CHO, (C 1 -C 4 alkyl) carbonyl, NH 2 , NH-C 1 -C 4 alkyl, N (C 1 -C 4 alkyl) 2 , pyrrolidino, morpholino, piperidino, SO 2 NH 2 , S0 2 N (C 1 -C 4 alkyl) 2 , pyrrolidinosulfonyl, giperidinosulfonyl or morpholinosulfonyl,
R 3 can also represent an NH 2 or NH-alkyl group. in C 1 -C 4 when R 4 = halogen and a hydrogen atom when R 4 represents an OH or C 1 -C 4 alkyloxy group; c) an aromatic group with a structure:
Figure imgb0022
 where R 2 and p have the same meanings as above, R ' 3 = OH, C 1 -C 4 alkyloxy or C 1 -C 4 alkyl and R 5 = NH 2 , NH-C 1 -C 4 alkyl, N (C 1 -C 4 alkyl) 2 , pyrrolidino, piperidino, morpholino, halogen or C 1 -C 4 alkyloxy, R ′ 3 possibly also representing a hydrogen atom when R 5 represents a C 1 alkyloxy group -C 4 ; or d) an aromatic group with a structure:
Figure imgb0023
 where R 2 has the same meaning as above; the compounds of formula (I) having the axial form (la):
Figure imgb0024
 where n = 2 or 3 and the ArCONH chain is in an equatorial position and the oxygen atom of the fragment
Figure imgb0025
 is in the axial position or the equatorial form (Ib):
Figure imgb0026
 where n = 2 or 3 and the ArCONH chain and the oxygen atom of the fragment
Figure imgb0027
 are both in an equatorial position; or being constituted by a mixture of the axial shape (Ia) and the equatorial shape (Ib). 2. Composés de structure (la) selon la revendication 1, pour lesquels l'ensemble (Ar-, R, n) prend l'une quelconque des significations suivantes :
Figure imgb0028
Figure imgb0029
Figure imgb0030
 2. Structural compounds (la) according to claim 1, for which the assembly (Ar-, R, n) takes any of the following meanings:
Figure imgb0028
Figure imgb0029
Figure imgb0030
 3. Composés de structure (Ib) selon la revendication 1, pour lesquels l'ensemble (Ar-, R, n) prend l'une quelconque des significations suivantes :
Figure imgb0031
Figure imgb0032
Figure imgb0033
 3. Structural compounds (Ib) according to claim 1, for which the assembly (Ar-, R, n) takes any of the following meanings:
Figure imgb0031
Figure imgb0032
Figure imgb0033
 4. Médicaments ayant notamment une activité sur le système nerveux central, caractérisés en ce qu'ils sont constitués par les composés selon l'une quelconque des revendications précédentes.4. Medicines having in particular an activity on the central nervous system, characterized in that they consist of the compounds according to any one of the preceding claims. 5. Composition pharmaceutique, caractérisée en ce qu'elle comprend à titre de principe actif au moins l'un des médicaments selon la revendication 4 en association avec un véhicule pharmaceutiquement acceptable.5. Pharmaceutical composition, characterized in that it comprises, as active principle, at least one of the medicaments according to claim 4 in combination with a pharmaceutically acceptable vehicle. 6. Procédé de préparation des composés selon la revendication 1 de formule (I), caractérisé en ce qu'il consiste en une oxydation des composés de formule :
Figure imgb0034
dans laquelle la chaîne ArCONH est en position équatoriale, n = 2 ou 3 et R et Ar ont la même signification que dans la revendication1, éventuellement suivie de la séparation des formes (la) et (Ib).6. Process for preparing the compounds according to claim 1 of formula (I), characterized in that it consists of an oxidation of the compounds of formula:
Figure imgb0034
 in which the chain ArCONH is in an equatorial position, n = 2 or 3 and R and Ar have the same meaning as in claim 1, possibly followed by the separation of the forms (la) and (Ib). 7. Procédé selon la revendication 6, caractérisé en ce que l'on réalise l'oxydation par mise en oeuvre d'un peracide.7. Method according to claim 6, characterized in that the oxidation is carried out by using a peracid. 8. Procédé selon la revendication 7, caractérisé en ce que le peracide est l'acide métachloroperbenzoique.8. Method according to claim 7, characterized in that the peracid is metachloroperbenzoic acid. 9. Procédé selon la revendication 6, caractérisé en ce que l'on réalise l'oxydation par mise en oeuvre d'un peroxyde.9. Method according to claim 6, characterized in that the oxidation is carried out by using a peroxide. 10. Procédé selon la revendication 9, caractérisé en ce que le peroxyde est l'eau oxygénée.10. Method according to claim 9, characterized in that the peroxide is hydrogen peroxide. 11. Procédé selon l'une quelconque des revendications 6 à 10, caractérisé en ce que la séparation des formes (Ia) et (Ib) est réalisée par chromatographie sur colonne.11. Method according to any one of claims 6 to 10, characterized in that the separation of the forms (Ia) and (Ib) is carried out by column chromatography. 12. Procédé selon la revendication 11, caractérisé en ce que la chromatographie est du type chromatographie liquide sur colonne de silice à haute ou moyenne pression.12. Method according to claim 11, characterized in that the chromatography is of the liquid chromatography type on a silica column at high or medium pressure.
EP84401032A 1983-05-20 1984-05-18 Aminocyclic n-oxide derivatives, process for their preparation and their therapeutical use Withdrawn EP0127529A3 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR8308350A FR2546169B1 (en) 1983-05-20 1983-05-20 N-OXIDES OF AMINOCYCLIC DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR APPLICATION IN THERAPEUTICS
FR8308350 1983-05-20

Publications (2)

Publication Number Publication Date
EP0127529A2 true EP0127529A2 (en) 1984-12-05
EP0127529A3 EP0127529A3 (en) 1987-10-14

Family

ID=9289014

Family Applications (1)

Application Number Title Priority Date Filing Date
EP84401032A Withdrawn EP0127529A3 (en) 1983-05-20 1984-05-18 Aminocyclic n-oxide derivatives, process for their preparation and their therapeutical use

Country Status (6)

Country Link
EP (1) EP0127529A3 (en)
JP (1) JPS6034966A (en)
AU (1) AU2799484A (en)
ES (1) ES532644A0 (en)
FR (1) FR2546169B1 (en)
ZA (1) ZA843757B (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4803199A (en) * 1982-06-29 1989-02-07 Peter Donatsch Pharmaceutically useful heterocyclic and carbocyclic acid esters and amides of alkylene bridged piperidines
WO2010113065A1 (en) 2009-03-28 2010-10-07 Braun Gmbh Gripping area for a working device

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE456502T1 (en) 2003-09-10 2010-02-15 Hitachi Construction Machinery CONSTRUCTION MACHINERY

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0013138A1 (en) * 1978-12-30 1980-07-09 Beecham Group Plc Azabicycloalkyl derivatives, a process for their preparation and pharmaceutical compositions containing them
GB2042522A (en) * 1979-01-16 1980-09-24 Delalande Sa Nor-tropane derivatives a process for preparing same and their application in therapeutics
GB2088364A (en) * 1980-11-07 1982-06-09 Delalande Sa Derivatives of nortropane and granatane
FR2499570A1 (en) * 1981-02-11 1982-08-13 Delalande Sa 3-Acylamino-8-arylmethyl-nortropane derivs. - useful as neuroleptic agents (NL 18.7.80)
EP0068700A1 (en) * 1981-06-29 1983-01-05 Beecham Group Plc Azobicycloalkylbenzamides, process for their preparation and pharmaceutical compositions containing them
EP0083737A1 (en) * 1981-12-15 1983-07-20 Beecham Group Plc N-azabicycloalkane benzamides, process for their preparation and pharmaceutical compositions containing them
EP0095262A1 (en) * 1982-05-11 1983-11-30 Beecham Group Plc Azabicycloalkane derivatives, their preparation and medicaments containing them
EP0096524A2 (en) * 1982-06-04 1983-12-21 Beecham Group Plc Bicyclic benzamides or anilides, process for their preparation, and pharmaceutical compositions containing them

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1586468A (en) * 1976-10-29 1981-03-18 Anphar Sa Piperidine derivatives
GB1575310A (en) * 1976-11-16 1980-09-17 Anphar Sa Piperidine derivatives
GB1574418A (en) * 1976-11-16 1980-09-03 Anphar Sa Piperidine derivatives

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0013138A1 (en) * 1978-12-30 1980-07-09 Beecham Group Plc Azabicycloalkyl derivatives, a process for their preparation and pharmaceutical compositions containing them
GB2042522A (en) * 1979-01-16 1980-09-24 Delalande Sa Nor-tropane derivatives a process for preparing same and their application in therapeutics
GB2088364A (en) * 1980-11-07 1982-06-09 Delalande Sa Derivatives of nortropane and granatane
FR2499570A1 (en) * 1981-02-11 1982-08-13 Delalande Sa 3-Acylamino-8-arylmethyl-nortropane derivs. - useful as neuroleptic agents (NL 18.7.80)
EP0068700A1 (en) * 1981-06-29 1983-01-05 Beecham Group Plc Azobicycloalkylbenzamides, process for their preparation and pharmaceutical compositions containing them
EP0083737A1 (en) * 1981-12-15 1983-07-20 Beecham Group Plc N-azabicycloalkane benzamides, process for their preparation and pharmaceutical compositions containing them
EP0095262A1 (en) * 1982-05-11 1983-11-30 Beecham Group Plc Azabicycloalkane derivatives, their preparation and medicaments containing them
EP0096524A2 (en) * 1982-06-04 1983-12-21 Beecham Group Plc Bicyclic benzamides or anilides, process for their preparation, and pharmaceutical compositions containing them

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4803199A (en) * 1982-06-29 1989-02-07 Peter Donatsch Pharmaceutically useful heterocyclic and carbocyclic acid esters and amides of alkylene bridged piperidines
US4910207A (en) * 1982-06-29 1990-03-20 Peter Donatsch Method of treating psychosis with N-quinuclidinyl-benzamides
US5017582A (en) * 1982-06-29 1991-05-21 Sandoz Ltd. Method of inducing a serotonin M receptor antagonist effect with N-quinuclidinyl-benzamides
WO2010113065A1 (en) 2009-03-28 2010-10-07 Braun Gmbh Gripping area for a working device

Also Published As

Publication number Publication date
FR2546169A1 (en) 1984-11-23
AU2799484A (en) 1984-11-22
FR2546169B1 (en) 1986-03-21
ZA843757B (en) 1985-01-30
ES8506310A1 (en) 1985-07-01
ES532644A0 (en) 1985-07-01
JPS6034966A (en) 1985-02-22
EP0127529A3 (en) 1987-10-14

Similar Documents

Publication Publication Date Title
EP0099789B1 (en) 3-aminoquinuclidin derivatives, process for their preparation and their use as therapeutical agents
FR2476088A2 (en) NOVEL NOR-TROPANE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
EP0005689B1 (en) Lactam-n-acetic acids, their amides, process for their preparation and therapeutic compositions containing them
FR2548666A1 (en) New nortropane and granatane derivatives, process for their preparation and their application in therapeutics
FR2495153A1 (en) NEW DIBENZAZEPINES, THEIR PREPARATION AND THEIR APPLICATION AS MEDICINES
EP0148167B1 (en) Quinoline derivatives, process for their preparation and pharmaceutical compositions containing them
EP0048705B1 (en) 2-(4-(diphenylmethylene)-1-piperidinyl)-acetic acids and their amides, their preparation and pharmaceutical preparations containing them
EP0061380A1 (en) Imidazo (1,2-a) pyrimidine derivatives, their preparation and their therapeutical use
EP0256936A1 (en) 4-Benzyl piperazine derivatives, their preparation and pharmaceutical compositions containing them
EP0178201B1 (en) Furo[3,2-c]pyridine derivatives, their preparation and their therapeutical use
EP0364350B1 (en) 4-Methyl-5[2-(4-phenyl-1-piperazinyl)-ethyl] thiazole derivatives, their preparation and pharmaceutical compositions containing them
EP0127529A2 (en) Aminocyclic N-oxide derivatives, process for their preparation and their therapeutical use
EP0089860A1 (en) Levogyrous isomer of mequitazine, process for its preparation and pharmaceutical preparations containing it
EP0077720A1 (en) Biphenyl alkyl carboxylated derivatives, process for their preparation and their use as medicines
EP0301936A1 (en) Piperidine derivatives, their preparation and their therapeutical use
EP0294258A1 (en) Hydrazine derivatives, process for obtaining them and pharmaceutical composition containing them
EP0079411B1 (en) Indoloquinolizine derivatives, process for their preparation and their therapeutic use
EP0123605B1 (en) N-cyclopropylmethyl-2-oxo-3-diparamethoxyphenyl-5,6-triazines, process for its preparation and their use as pharmaceutical preparations
EP0043811B1 (en) Indolo-naphthyridines and their use as medicaments
EP0027412A1 (en) Pyridine derivatives, process for their preparation and medicaments containing them
EP0017523B1 (en) Dithiepinno (1,4)(2,3-c) pyrrol derivatives, their preparation and pharmaceutical compositions containing them
FR2518992A1 (en) 1-Amino-omega-aryloxy substd. ethane and propane derivs. - with calcium antagonising activity e.g. for treating angina
EP0347305B1 (en) [(Aryl-4-piperazinyl-1)-2-ethoxy]-3 p cymene, the ortho-, meta-, para-monosubstituted or disubstituted phenyl ring derivatives, process for their preparation and medicaments containing the same as the active principle
EP0082058A1 (en) Ethers of oximes of 1-pyridyl-3-pentanone, process for their preparation and their use as a drug
EP0100257B1 (en) Aminoalkyl naphthalene derivatives, their salts, process for their preparation and the therapeutical use of these derivatives and salts

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Designated state(s): BE CH DE FR GB IT LI LU NL SE

PUAL Search report despatched

Free format text: ORIGINAL CODE: 0009013

AK Designated contracting states

Kind code of ref document: A3

Designated state(s): BE CH DE FR GB IT LI LU NL SE

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19870602

RIN1 Information on inventor provided before grant (corrected)

Inventor name: BUCHER, BERNARD

Inventor name: DOSTERT, PHILIPPE

Inventor name: IMBERT, THIERRY